October 28, 2021

I, Science

The science magazine of Imperial College

Experimental neuroscience which studies dopamine and the brain's reward system can shed light on drug addiction, how it works, and how to treat it.

Perhaps the most famous chemical compounds in our bodies, chances are you’ve heard of dopamine. But exactly what it is has often been misunderstood, as well as whether or not it is directly responsible for the sense of pleasure and reward which reinforces many of human behaviours, from exercising to eating to taking recreational drugs.  In this feature, Tim Davies takes us through some key points of the importance of dopamine, how it works, and how it can help us to understand and prevent chronic addictions.
Dopamine molecule
There are a number of things animals need to do to survive. To function they have to eat and drink, and for their genes to persist they must reproduce. As such it is crucial that animals are not only motivated to perform these actions, but that they prioritize them above all other things. Animals have therefore evolved neural mechanisms to reinforce rewarding behaviours, and a key aspect of this reinforcement is the organic chemical dopamine.

Dopamine is a signalling molecule in the brain, or neurotransmitter, that is released following a rewarding stimulus. A group of neurons in a part of the midbrain called the ventral tegmental area (VTA) send axons to an area called the nucleus accumbens (NAc), releasing dopamine. Drugs hijack this natural reward pathway. Though drugs have wide ranging and varied pharmacological effects on the body, every drug from cocaine to nicotine ultimately causes an increase in dopamine in the NAc.

But the strongest proof that dopamine is the key to addiction comes from a revolutionary technique in neuroscience called optogenetics.

Using optogenetics researchers can selectively switch on or off specific groups of neurons in the brain using light. By exciting pathways that release dopamine in the NAc it’s possible to reproduce the same addictive behaviours shown by mice when they are given drugs.

But how exactly does the release of dopamine result in addictive behaviours? There are several theories that try to explain this.

One idea is that dopamine release causes pleasure. This is known as the Hedonia hypothesis. It is very popular perhaps because it makes intuitive sense; rewarding stimuli make us feel good, so if dopamine release is the key to reward, dopamine must make us feel good.

However, a number of experiments in mice show that animals unable to produce dopamine still show a preference for rewarding stimuli, such as artificially sweetened water, to non rewarding ones. There is also the puzzling case of nicotine, which has an addictiveness that has been compared to that of heroin, despite producing little or no euphoria for the user.

One interesting observation of these experiments is that while animals lacking dopamine still prefer rewarding stimuli, they seem to lack the motivation to pursue them. The distinction here is between “liking” and “wanting”. And it’s an important distinction. As the casual drug user transitions from occasional user to full-blown addict they often report “enjoying” drugs less and less, and “needing” them more and more. The theory describing the wanting or craving caused by dopamine release in the NAc is incentive salience.

Drug addiction is a disease characterized by two things: firstly, a need to use the drug in spite of its negative consequences, and secondly, a pattern of chronic relapse that persists even after use of the drug has stopped. It’s known that if recovering addicts come in contact with cues associated with their former drug use it increases the likelihood of relapse. Incentive salience helps explain this phenomenon. Through the release of dopamine, rewarding and non-rewarding stimuli become associated, and in this way a drug-associated object such as a spoon becomes a “secondary reinforcer” of drug use.

But how are these associations made? Well, it seems dopamine might actually be important for reward learning. A set of experiments performed by Schultz and colleagues are key to our understanding of dopamine’s role in reward and addiction. They measured the firing of dopamine neurons in the brains of monkeys given sweet juice rewards. Unsurprisingly, when monkeys were given the reward their dopamine neurons showed a burst of activity. More interesting was the finding that this burst of activity comes only when a reward is unexpected. Furthermore if a reward is expected but doesn’t arrive, the activity of these neurons drops below baseline levels. These neurons therefore respond to differences between an expected and obtained reward, the so called “prediction error”.
The research shows us that when an outcome is better than expected there is a burst of activity and a release of dopamine. In this way actions performed by an animal that result in a good outcome are reinforced. Over time reinforced actions become habitual. Drugs are able to cause massive dopamine release and are therefore excellent habit formers.

However, in order to able to use knowledge of the dopamine reward system to treat addiction we must first gain an insight into how this brain circuitry changes as people make the transition from occasional drug user to an addict.

A recent technique called fast scan cyclic voltammetry (FSCV) allows detection of dopamine release in vivo at a time scale of less than a second, and therefore allows us to accurately track the dynamics of dopamine release. One recent study measured the release of dopamine in rats over time as they self-administered cocaine. They found that surprisingly, dopamine release decreased as their rate of cocaine intake increased. Furthermore by administering a dopamine analogue (a compound with similar properties) called L-DOPA, the group found they could actually reverse the increase in drug use that occurred over time.

This finding was somewhat in contradiction to some modern theories of addiction which hypothesised that over time reward pathways in the addict might become hyper-sensitized, increasing the response to the drug and drug associated stimuli, and driving the process of the establishment of drug craving. It does, however, make sense with what we know about dopamine and its role in reward learning. After all, if the amount of dopamine released decreases the more a reward is expected, the more a drug would need to be administered to produce the same effect. Either way, thanks to more advanced techniques we are increasingly gaining an insight into the dynamics of the dopamine reward system.

With this understanding comes the exciting potential to target the system, in order to try and reduce drugs’ hold over addicts. Despite this knowledge however, current treatments for e.g. opioid and nicotine addiction are focused mainly on reduction or replacement of the drug. In the case of opioid addiction, analogues such as methadone are prescribed to try and reduce the withdrawal and cravings that are the key driver to relapse. Similarly, naltrexone is a drug used in the treatment of alcohol and opioid addiction that blocks opioid receptors, and although its exact mode of action is not know, it is likely its effects are ultimately through the dopaminergic pathways.

Therefore although there is now strong evidence that dopamine pathways in the midbrain have a casual role both in reward learning and in driving the addictive properties of drugs, this fact has yet to be exploited to target these systems directly for the treatment of addiction. New techniques in the field of neuroscience are shedding more and more light on the reward pathways in the brain, allowing us to target particular groups of neurons and track how the release of chemical signals in the brain such as dopamine control behaviour. The hope is that by using this knowledge to develop treatments which more directly target reward systems in the brain, we will be able to reduce the hold drugs can exert over our behaviour.

Tim Davies is a research postgraduate with a background in neuroscience. 

Image: zizi_mentos/shutterstock, Alice Vacca/shutterstock